1. Field of the Invention
The present invention generally relates to down-regulation of CCR5 expression, and more particularly, to compositions comprising at least one G1 phase arresting agent that exhibits down-regulation of surface receptor CCR5 expression thereby treating human diseases in which CCR5 receptors plays an adverse role.
2. Background of the Related Art
The human immunodeficiency virus (HIV) has been implicated as the primary cause of the slowly degenerative immune system disease termed acquired immune deficiency syndrome (AIDS). There are at least two distinct types of HIV: HIV-1 and HIV-2. In humans, HIV replication occurs prominently in CD4 T lymphocyte populations, and HIV infection leads to depletion of this cell type and eventually to immune incompetence, opportunistic infections, neurological dysfunctions, neoplastic growth, and ultimately death.
HIV is a member of the lentivirus family of retroviruses. Retroviruses are small-enveloped viruses that contain a single-stranded RNA genome, and replicate via a DNA intermediate produced by a virally encoded reverse transcriptase, an RNA-dependent DNA polymerase.
The HIV viral particle comprises a viral core, composed in part of capsid proteins, together with the viral RNA genome and those enzymes required for early replicative events. Myristylated gag protein forms an outer shell around the viral core, which is, in turn, surrounded by a lipid membrane envelope derived from the infected cell membrane. The HIV envelope surface glycoproteins are synthesized as a single 160 kilodalton precursor protein, which is cleaved by a cellular protease during viral budding into two glycoproteins, gp41 and gp120. gp41 is a transmembrane glycoprotein and gp120 is an extracellular glycoprotein, which remains non-covalently associated with gp41, possibly in a trimeric or multimeric form.
HIV is targeted to CD4 cells because a CD4 cell surface protein (CD4) acts as the cellular receptor for the HIV-1 virus. Viral entry into cells is dependent upon gp120 binding the cellular CD4 receptor molecules, explaining HIV's tropism for CD4 cells, while gp41 anchors the envelope glycoprotein complex in the viral membrane. CCR5 serves as a co-receptor for the infection of CD4 cells by nonsyncytium-inducing (NSI) strains of HIV-1.
Expression of the CCR5 receptor on T cells is dependent on the activation state of the cells. Resting lymphocytes do not express CCR5, however, upon activation, CCR5 is expressed. The importance of CCR5 for initial transmission of HIV-1 is highlighted by the fact that individuals lacking expression of CCR5 (the CCR5-Δ32 homozygous genotype) are usually resistant to infection (Liu, et al., 1996). In addition, recent studies show that CCR5 cell-surface density correlates with disease progression in infected individuals (Lin, et al., 2002).
Other disorders and the progression of effects have been found to be related to expression of the CCR5 receptor. For example, allograft rejection occurs as a result of extravasation of recipient mononuclear cells into the allograft, a process that is mediated by expression of CCR5 on the infiltrating mononuclear cells. Asthma studies using murine models of allergic airway disease have shown that CCR5 likely plays an important role in airway inflammation. Further, rheumatoid arthritis is characterized by the infiltration of the synovial membrane with mononuclear cells and CCR5 seems to play a role due to the high levels of CCR5 expression found in infiltrated lymphocytes. Interestingly, mononuclear cells present in the active demyelinating plaques characteristic of subject suffering from multiple sclerosis also show high levels of CCR5 expression.
Thus, it would be advantageous to identify compounds that reduce or inhibit the expression of CCR5 surface receptors on mononuclear cells and administer such compounds to effect treatment of disorders related to the expression of CCR5 surface receptors.